The Notch-signaling pathway is a system for cell-to-cell communication used by a wide range of eukaryotes for many biological processes, such as differentiation, proliferation, and homeostasis. Delta like 4 (Dl4) or delta-like ligand 4 (Dll4) (hereinafter “Dll4”) is a member of the Delta family of Notch ligands which exhibits highly selective expression by vascular endothelium (Shutter et al. (2000) Genes Develop. 14:1313-1318). Dll4 is a ligand for Notch receptors, including Notch1 and Notch 4. The amino acid sequence for human Dll4 is depicted in SEQ ID NO:9. Given the important role that the Dll4-Notch signaling pathway plays in the regulation of angiogeneisis and its implication in human health and medicine, it is desired to develop and deploy Dll4-based medicaments. One such Dll4-based medicament is a therapeutic antibody specific to Dll4.
Methods to produce antibodies useful as human therapeutics include generation of chimeric antibodies and humanized antibodies (see, for example, U.S. Pat. No. 6,949,245). See, for example, WO 94/02602 (Abgenix) and U.S. Pat. No. 6,596,541 (Regeneron Pharmaceuticals), which publications are herein specifically incorporated by reference, describing methods of generating nonhuman transgenic mice capable of producing human antibodies. U.S. Pat. Nos. 7,488,806, 7,534,868, and 7,919,593, and U.S. Patent Application No. U.S. 2011-0150905A1 disclose antibodies to human Dll4, and are incorporated in their entirety herein by reference.
Therapeutic antibodies must be formulated in a manner that not only makes the antibodies suitable for administration to patients, but also in a manner that maintains their stability during storage and subsequent use. For example, therapeutic antibodies in liquid solution are prone to fragmentation, precipitation, aggregation, and undesired chemical modifications unless the solution is formulated properly. The stability of an antibody in liquid formulation depends not only on the kinds of excipients used in the formulation, but also on the amounts and proportions of the excipients relative to one another. Furthermore, other considerations aside from stability must be taken into account when preparing a liquid antibody formulation. Examples of such additional considerations include the viscosity of the solution and the concentration of antibody that can be accommodated by a given formulation, and the visual quality or appeal of the formulation. Thus, when formulating a therapeutic antibody, great care must be taken to arrive at a formulation that remains stable, contains an adequate concentration of antibody, and possesses a suitable viscosity as well as other properties which enable the formulation to be conveniently administered to patients.
Antibodies to Dll4 are one example of a therapeutically relevant macromolecule that requires proper formulation. Although some anti-Dll4 antibodies are known, there nonetheless remains a need in the art for novel pharmaceutical formulations comprising anti-Dll4 antibodies that are sufficiently stable and suitable for administration to patients.